In patients with nonalcoholic fatty liver disease (NAFLD), a liver biopsy remains the only reliable way to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH). Noninvasive methods are urgently needed. Increasing evidence suggests hepatocyte apoptosis is a key mediator of liver injury in NAFLD. The aim of this study was to quantify hepatocyte apoptosis in plasma from patients with NAFLD and correlate it with histological severity. Plasma was obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy. Histology was assessed blindly. Caspase-3-generated cytokeratin-18 fragments were measured in situ via immunohistochemistry and in vivo using a novel enzyme-linked immunosorbent assay. Plasma cytokeratin-18 fragments were markedly in-

The aims of this study were to determine whether combining features of a western lifestyle in mice with trans fats in a high-fat diet, high-fructose corn syrup in the water, and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Male C57BL/6 mice fed ad libitum high-fat chow containing trans fats (partially hydrogenated vegetable oil) and relevant amounts of a high-fructose corn syrup (HFCS) equivalent for 1-16 wk were compared with mice fed standard chow or mice with trans fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. By 16 wk, trans fat-fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma alanine aminotransferase levels increased, as did liver TNF-alpha and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 wk, respectively. Plasma insulin, resistin, and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans fats with lard established that trans fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity, and impaired insulin sensitivity. Combining risk factors for the metabolic syndrome by feeding mice trans fats and HFCS induced histological features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation.

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barrett’s esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Background The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of NASH. Methods 55 adults with biopsy-confirmed NASH were randomized to receive PTX at a dose of 400mg three times a day (n=26) or placebo (n=29) over 1 year. The primary efficacy endpoint was defined as improvement on histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥ 2 points in the NAFLD activity score (NAS). Results After 1 year, intention-to-treat analysis showed a decrease of >=2 points in the NAS in 38.5% of patients on PTX vs 13.8% of those on placebo (p=0.036). Per protocol analysis, a decrease of ≥ 2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (p=0.01). The mean change in NAS score from baseline was −1.6 in the PTX group, vs −0.1 in the placebo group (p<0.001). PTX significantly improved steatosis (mean change in score −0.9 vs −0.04 with placebo, p<0.001) and lobular inflammation (median change −1 vs 0 with placebo, p=0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was −0.2 among those on PTX versus +0.4 among those on placebo, p=0.038). Although not statistically significant (p=0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. Conclusion PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH (ClinicalTrials.gov number NCT00590161).

This article is available online at http://www.jlr.org S. L. Hazen. Mass spectrometric profi ling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J. Lipid Res. 2010. 51: 3046-3054.Supplementary key words oxidized fatty acids • mass spectrometry • chiral mass spectrometry Nonalcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease affecting both adults and children, and it is strongly associated with obesity and insulin resistance ( 1, 2 ). One in three adults and one in ten children or adolescents in the United States have hepatic steatosis, a stage within the spectrum of NAFLD that is characterized by triglyceride accumulation in liver cells and follows a benign, nonprogressive clinical course ( 3, 4 ). Nonalcoholic steatohepatitis (NASH) is defi ned as lipid accumulation with evidence of cellular damage, infl ammation, and different degrees of scarring or fi brosis ( 5 ). NASH is a serious condition as approximately 25% of these patients progress to cirrhosis and its feared complications of portal hypertension, liver failure, and hepatocellular carcinoma ( 6-8 ).At present, the available noninvasive markers for NAFLD include a set of clinical signs and symptoms, nonspecifi c laboratory and radiological imaging tests, and combinations of clinical and blood test results ( 9 ). Although several of these markers are generally useful for the diagnostic evaluation of a patient with suspected Abstract Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the pathways that contribute to oxidative damage in vivo are poorly understood. Our aims were to defi ne the circulating profi le of lipid oxidation products in NAFLD patients, the source of these products, and assess whether their circulating levels refl ect histological changes in the liver. The levels of multiple structurally specifi c oxidized fatty acids, including individual hydroxy-eicosatetraenoic acids (HETE), hydroxy-octadecadenoic acids (HODE), and oxo-octadecadenoic acids (oxoODE), were measured by mass spectrometry in plasma at time of liver biopsy in an initial cohort of 73 and a validation cohort of 49 consecutive patients. Of the markers monitored, 9-and 13-HODEs and 9-and 13-oxoODEs, products of free radical-mediated oxidation of linoleic acid (LA), were signifi cantly elevated in patients with nonalcoholic steatohepatitis (NASH), compared with patients with steatosis. A strong correlation was revealed between these oxidation products and liver histopathology (infl ammation, fi brosis, and steatosis). Further analyses of HODEs showed equivalent R and S chiral distribution. A risk score for NASH (oxNASH) was developed in the initial clinical cohort and shown to have high diagnostic accuracy for NASH versus steatosis in the independent validation cohort. Subjects with elevated oxNASH levels (top tertile) were 9.7-fold ( P < 0.0001) more likely to have NASH than those with low levels (b...

The growing demand for liver transplantation and the concomitant scarcity of cadaveric livers have increased the need for living donor liver transplantation (LDLT). Ensuring the safety of donors and recipients is critical. The preoperative identification of the vascular and biliary tract anatomy with 3-dimensional (3D) printing may allow better preoperative surgical planning, avert unnecessary surgery in patients with potentially unsuitable anatomy, and thereby decrease the complications of liver transplant surgery. We developed a protocol and successfully 3D-printed synthetic livers (along with their complex networks of vascular and biliary structures) replicating the native livers of 6 patients: 3 living donors and 3 respective recipients who underwent LDLT. To our knowledge, these are the first complete 3D-printed livers. Using standardized preoperative, intraoperative, and postoperative assessments, we demonstrated identical anatomical and geometrical landmarks in the 3D-printed models and native livers. Three-dimensional (3D) printing is a process for making a solid 3D object of virtually any shape from a digital model. A 3D printer works as an ordinary office printer, but instead of placing a single layer of ink on paper, the machine lays down successive thin layers of a material to form a 3D object that replicates the original one. 1 The growing demand for liver transplantation and the concomitant shortage of cadaveric livers have led to a rise in living donor liver transplantation (LDLT), in which resection of the right or left liver lobe is performed for the purpose of liver transplantation. 2 Living donors are healthy individuals, so ensuring their safety is of paramount importance. There have been a number of reported donor deaths worldwide and a substantial number of donor morbidities, so there is a need for measures to optimize donor safety. 3 Many of these morbidities are attributable to incomplete preoperative anatomical characterization of vascular and biliary structures and inaccurate estimates of the liver volume; these data are needed to determine the extent of the resection. This information provides a road map, and its accuracy has improved with the introduction of radiological software able to provide 3D visualization of liver structures. 4,5 3D imaging has the ability to better demonstrate the 3D relationships between vital vascular and biliary structures and the surrounding parenchyma in comparison with conventional computed tomography (CT) or magnetic resonance imaging (MRI). 3D imaging Additional Supporting Information may be found in the online version of this article.

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Context.-High-resolution scanning technology provides an opportunity for pathologists to make diagnoses directly from whole slide images (WSIs), but few studies have attempted to validate the diagnoses so obtained.Objective.-To compare WSI versus microscope slide diagnoses of previously interpreted cases after a 1-year delayed re-review (''wash-out'') period.Design.-An a priori power study estimated that 450 cases might be needed to demonstrate noninferiority, based on a null hypothesis: ''The true difference in major discrepancies between WSI and microscope slide review is greater than 4%.'' Slides of consecutive cases interpreted by 2 pathologists 1 year prior were retrieved from files, and alternate cases were scanned at original magnification of 320. Each pathologist reviewed his or her cases using either a microscope or imaging application. Independent pathologists identified and classified discrepancies; an independent statistician calculated major and minor discrepancy rates for both WSI and microscope slide review of the previously interpreted cases.Results.-The 607 cases reviewed reflected the subspecialty interests of the 2 pathologists. Study limitations include the lack of cytopathology, hematopathology, or lymphoid cases; the case mix was not enriched with difficult cases; and both pathologists had interpreted several hundred WSI cases before the study to minimize the learning curve. The major and minor discrepancy rates for WSI were 1.65% and 2.31%, whereas rates for microscope slide reviews were 0.99% and 4.93%.Conclusions.-Based on our assumptions and study design, diagnostic review by WSI was not inferior to microscope slide review (P , .001).